Problem to be Solved: Triple-negative breast cancer (TNBC) is a deadly disease that accounts for 15-20% of all diagnosed breast cancers worldwide. Metastatic relapse of TNBC carries a poorer prognosis and lower survival rate compared to other breast cancer subtypes. Therefore, identifying novel targets and new therapeutics to treat patients diagnosed with TNBC remains a significant priority of the National Institutes of Health. Product and Long-Term Goal: Nanometics is developing a once daily, oral therapeutic, dubbed MTDIA for the treatment of TNBC. MTDIA inhibits a novel target, 5 -methylthioadenosine phosphorylase (MTAP), and disrupts biochemical pathways crucial for cancer growth. Technical Innovation: The MTAP enzyme is a promising new target for anti-cancer therapeutics because its systemic inhibition results in the whole-body accumulation of the 5'-methylthioadenosine (MTA) metabolite, which alters known anti-cancer pathways. Oral dosing with MTDIA is effective against both MTAP-positive and MTAP-negative tumors, causing a significant reduction in primary tumor growth rates and regression of existing tumors. Phase I Hypotheses: The hypotheses that will be tested during the Phase I STTR experiments are that: 1) clinically efficacious oral doses of MTDIA will be tolerable (non-toxic) in rat models, and 2) MTDIA will suppress tumor growth rates in rats with similar efficacy as demonstrated in mice (see Preliminary Results). Specific Aims: The specific aims of this Phase I STTR are to: 1) determine that pharmacologically relevant oral doses of MTDIA are non-toxic and tolerable in rats, and 2) determine that MTDIA suppresses TNBC tumors in rats to the same extent as has been demonstrated in mouse models. Phase II: Phase II STTR studies will establish toxicity of MTDIA in rats and beagle dogs under GLP guidelines. Commercial Opportunity: The global market for breast cancer therapeutics is forecast to reach $13.86 billion by 2017. Because the treatment options for metastatic relapse of TNBC are limited, there remains a significant need for new drugs that work through novel modes of action.